Circulating lymphocytes respond to the presence of foreign antigens by undergoing blastogenesis. This allows for a major change in cell number and aids in neutralizing the effect of the antigen. It is one way that the immune system meets the challenge of disease or presence of foreign tissue. This response is seen when tissue transplants occur and can result in tissue rejection.
The fetus is also foreign to the host (mother) since it has antigens that are contributed by the paternal genome. Mechanisms preventing maternal rejection of the semiallogenic fetus are not well understood. However, the maternal immune system is fully capable of rejecting paternal antigens expressed by the conceptus and it is well documented in sheep that the uterus is capable of tissue transplant rejection and that the fetus therefore must regulate the immune system in a protective way. Proposed mechanisms include secretion by the fetus of proteinaceous products which act to suppress the immune system.
Ovine Trophoblast Protein-1 (oTP-1) is a conceptus secretory product produced by the ovine conceptus between days 13 and 21 after conception (REF). It is known to have antiluteolytic properties, in particular it prevents functional regression of the corpus luteum, and it maintains progesterone in the circulation and thus maintains pregnancy. The protein does not leave the uterus but instead alters production and/or secretion of prostaglandin F-2, the compound responsible for regresssion of the corpus luteum. oTP-1 has a high degree of homology with the interferon alpha family and possesses antiviral activity. oTP-1 suppresses mitogenesis in lymphocytes stimulated with concanavalin A (CON A), pokeweed mitogen (PWK) or phytohemagglutinin (PHA).
A bovine trophoblast protein (bTP-1) with properties similar to those of oTP-1 also has been identified. It is interferon-like and capable of extending the life-span of the corpus luteum when introduced into the uterus or injected intramuscularly into cattle. It would therefore be of interest to develop compositions and methods of using as a means for maintaining the conceptus and enhancing conception rates and additionally whether they may have immune suppressive properties.
Relevant Literature
Specific proteins secreted from endometrial tissues during early and late pregnancy in the ewe, were found to regulate in vitro lymphoblastogenesis (Staples, Biol. Reprod. (1980) 22:675-685; Segerson, Biol. Reprod. (1981) 25:77-84; Staples et al., Placenta (1983) 4:125-132; Segerson et al., Biol. Reprod. (1984) 30:1175-1186; Hansen et al., Biol. Reprod. (1987) 36:393-403). Conceptus tissue secretory products, produced when embryos were in the third week of age, suppressed lymphoblastogenesis (Murray et al., Amer. J. Reprod. Immunol. and Microbiol. (1987) 14:38-44). The suppressive substance was a high-molecular-weight glycoprotein (molecular weight of &gt;660,000 daltons). Similarly, secretions from the nonpregnant uterus were effective in suppressing lymphoblastogenesis. Suppression was greatest near day 14 of the cycle (Segerson, Biol. Reprod. (1981) 25:77-84). Segerson (Biol. Reprod. (1988) 38:256-263) showed that uterine luminal protein (UPL) secretions of day 14 of pregnancy in the ewe suppressed blastogenesis of interleukin-2 (IL-2) -dependent T-lymphocytes. Such an effect has also been shown for factors in the sera of pregnant humans (Nicholas et al., Clin. Exp. Immunol. (1984) 58:587-595; Domingo et al., J. Reprod. Immunol. (1985) 8:97-110). A specific human placenta human placental protein, Placental Protein 14 (pp 14), has been shown to exhibit suppressive lymphoblastogenic activity (Bolton et al., The Lancet (1987) 1987:593-595).
Newton et al., (Am. J. Reprod. Immunol. (1989) 19:49-67) showed that sheep conceptus secretory proteins contained two immunosuppressive fractions. One fraction was identified as oTP-1 and the other as a high molecular weight glycoprotein. Suppression of elactogenesis by either protein was not reversed by addition of IL-2 when PWM was the mitogen. IL-2 induced proliferation of lymphocytes was suppressed by treatment with HAWG or oTP-1.
The subject of maternal recognition of pregnancy has been reviewed by Thatcher et al. (J. 15 Anim. Sci. (62(Suppl 2):25). Early work on this subject showed that ovine embryo homogenate, when infused into the uterus of sheep during the estrous cycle, would extend the life span of corpora luteu (Rowson and Moore, J. Reprod. Fert. (1967) 13:511. When infusions were stopped the animals returned to estrus. A similar study was conducted in the cow by Northey and French (J. Animal Sci. (1980) 50:298). They concluded that an embryo must be present in the uterus by the 16th day of the estrous cycle if corpora lutea, and thus higher circulating levels of progesterone, are to be maintained beyond a normal cycle length of 21 days. Certain proteins isolated from the ovine conceptus have been shown to extend the length of the estrous cycle. Martal et al. (J. Reprod. Fertil. (1979) 56:63) showed this when they infused trophoblastin into the uterus of the ewe during the estrous cycle. Godkin et al. (J. Reprod. Fert. (1984) 71:57) have found that ovine trophoblast protein-1 (oTP-1) would do the same thing. The biological response to both of these proteins was similar; the cycle length was extended for varying times from approximately 20 to more than 45 days in individual animals. The latter protein is not secreted by the conceptus after 24 days of age.